Abstract 2006: Sequencing of mismatch repair deficient tumors identifies a synthetic lethal interaction with other DNA repair pathways.

2013 ◽  
Author(s):  
Betül T. Yesilyurt ◽  
Hui Zhao ◽  
Xavier Sagaert ◽  
Lieve Coenegrachts ◽  
Zeynep Kalender ◽  
...  
Keyword(s):  
Dna Repair ◽  
Mismatch Repair ◽  
Synthetic Lethal Interaction ◽  
Synthetic Lethal ◽  
Repair Pathways

scholarly journals RecQ helicases in DNA repair and cancer targets

2020 ◽  
Vol 64 (5) ◽  
pp. 819-830
Author(s):  
Joseph A. Newman ◽  
Opher Gileadi
Keyword(s):  
Dna Repair ◽  
Small Molecules ◽  
Atp Hydrolysis ◽  
Cancer Therapeutics ◽  
Genome Integrity ◽  
Mechanistic Study ◽  
Synthetic Lethal ◽  
Recq Helicases ◽  
Repair Pathways ◽  
Higher Eukaryotes

Abstract Helicases are enzymes that use the energy derived from ATP hydrolysis to catalyze the unwinding of DNA or RNA. The RecQ family of helicases is conserved through evolution from prokaryotes to higher eukaryotes and plays important roles in various DNA repair pathways, contributing to the maintenance of genome integrity. Despite their roles as general tumor suppressors, there is now considerable interest in exploiting RecQ helicases as synthetic lethal targets for the development of new cancer therapeutics. In this review, we summarize the latest developments in the structural and mechanistic study of RecQ helicases and discuss their roles in various DNA repair pathways. Finally, we consider the potential to exploit RecQ helicases as therapeutic targets and review the recent progress towards the development of small molecules targeting RecQ helicases as cancer therapeutics.

scholarly journals A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments

PLoS ONE ◽  
2015 ◽  
Vol 10 (5) ◽  
pp. e0125482 ◽  
Author(s):  
Kareem N. Mohni ◽  
Petria S. Thompson ◽  
Jessica W. Luzwick ◽  
Gloria G. Glick ◽  
Christopher S. Pendleton ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Synthetic Lethal ◽  
Repair Pathways

scholarly journals NR1D1 regulation by Ran GTPase via miR4472 identifies an essential vulnerability linked to aneuploidy in ovarian cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Zied Boudhraa ◽  
Kossay Zaoui ◽  
Hubert Fleury ◽  
Maxime Cahuzac ◽  
Sophie Gilbert ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Critical Role ◽  
Inverse Correlation ◽  
Dna Damages ◽  
Ran Gtpase ◽  
Synthetic Lethal ◽  
Damage Repair ◽  
Repair Pathways

AbstractWhile aneuploidy is a main enabling characteristic of cancers, it also creates specific vulnerabilities. Here we demonstrate that Ran inhibition targets epithelial ovarian cancer (EOC) survival through its characteristic aneuploidy. We show that induction of aneuploidy in rare diploid EOC cell lines or normal cells renders them highly dependent on Ran. We also establish an inverse correlation between Ran and the tumor suppressor NR1D1 and reveal the critical role of Ran/NR1D1 axis in aneuploidy-associated endogenous DNA damage repair. Mechanistically, we show that Ran, through the maturation of miR4472, destabilizes the mRNA of NR1D1 impacting several DNA repair pathways. We showed that NR1D1 interacts with both PARP1 and BRCA1 leading to the inhibition of DNA repair. Concordantly, loss of Ran was associated with NR1D1 induction, accumulation of DNA damages, and lethality of aneuploid EOC cells. Our findings suggest a synthetic lethal strategy targeting aneuploid cells based on their dependency to Ran.

scholarly journals DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1713 ◽  
Author(s):  
Kristyna Tomasova ◽  
Andrea Cumova ◽  
Karolina Seborova ◽  
Josef Horak ◽  
Kamila Koucka ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Mismatch Repair ◽  
Therapy Outcome ◽  
Repair System ◽  
End Joining ◽  
Ample Evidence ◽  
Repair Pathways ◽  
Non Homologous End Joining ◽  
Risk Prognosis

There is ample evidence for the essential involvement of DNA repair and DNA damage response in the onset of solid malignancies, including ovarian cancer. Indeed, high-penetrance germline mutations in DNA repair genes are important players in familial cancers: BRCA1, BRCA2 mutations or mismatch repair, and polymerase deficiency in colorectal, breast, and ovarian cancers. Recently, some molecular hallmarks (e.g., TP53, KRAS, BRAF, RAD51C/D or PTEN mutations) of ovarian carcinomas were identified. The manuscript overviews the role of DNA repair machinery in ovarian cancer, its risk, prognosis, and therapy outcome. We have attempted to expose molecular hallmarks of ovarian cancer with a focus on DNA repair system and scrutinized genetic, epigenetic, functional, and protein alterations in individual DNA repair pathways (homologous recombination, non-homologous end-joining, DNA mismatch repair, base- and nucleotide-excision repair, and direct repair). We suggest that lack of knowledge particularly in non-homologous end joining repair pathway and the interplay between DNA repair pathways needs to be confronted. The most important genes of the DNA repair system are emphasized and their targeting in ovarian cancer will deserve further attention. The function of those genes, as well as the functional status of the entire DNA repair pathways, should be investigated in detail in the near future.

scholarly journals Targeting the Fanconi Anemia Pathway to Identify Tailored Anticancer Therapeutics

Anemia ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Chelsea Jenkins ◽  
Jenny Kan ◽  
Maureen E. Hoatlin
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Therapeutics ◽  
Core Complex ◽  
Synthetic Lethal ◽  
Interstrand Cross Links ◽  
Cross Links ◽  
Repair Pathways ◽  
Repair Genes

The Fanconi Anemia (FA) pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs). The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways. Selective killing of cancer cells with an intact FA pathway but deficient in certain other DNA repair pathways is an emerging approach to tailored cancer therapy. Inhibiting the FA pathway becomes selectively lethal when certain repair genes are defective, such as the checkpoint kinase ATM. Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

scholarly journals Targeting DNA Repair and Chromatin Crosstalk in Cancer Therapy

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 381
Author(s):  
Danielle P. Johnson ◽  
Mahesh B. Chandrasekharan ◽  
Marie Dutreix ◽  
Srividya Bhaskara
Keyword(s):  
Dna Repair ◽  
Cancer Therapy ◽  
Therapeutic Intervention ◽  
Synthetic Lethality ◽  
Checkpoint Proteins ◽  
Cellular Processes ◽  
Repair Pathways ◽  
Made In

Aberrant DNA repair pathways that underlie developmental diseases and cancers are potential targets for therapeutic intervention. Targeting DNA repair signal effectors, modulators and checkpoint proteins, and utilizing the synthetic lethality phenomena has led to seminal discoveries. Efforts to efficiently translate the basic findings to the clinic are currently underway. Chromatin modulation is an integral part of DNA repair cascades and an emerging field of investigation. Here, we discuss some of the key advancements made in DNA repair-based therapeutics and what is known regarding crosstalk between chromatin and repair pathways during various cellular processes, with an emphasis on cancer.

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